Sleep and wakefulness are regulated by an intricate interplay of multiple systems originating in the brainstem, hypothalamus, and basal forebrain (BF) that are under both circadian and homeostatic control. The circadian regulation is important for the timing of sleep, and the homeostatic regulation drives the intensity of sleep, based on the duration and quality of preceding wakefulness. The ascending arousal systems mediate their effects on wakefulness and cortical activity via a thalamic and an extrathalamic route. The extrathalamic route through the BF sends projections to the entire brain and could be involved in sleep homeostasis, because during prolonged wakefulness or sleep deprivation (SD), the extracellular build-up of adenosine specifically inhibits cholinergic neurons of the BF. In this thesis I explored the role of the ascending arousal systems in the regulation of sleep, wakefulness, and cortical activation mediated by the BF. Polysomnographic recordings with or without combined in vivo microdialysis in freely behaving animals were used, to test the following hypotheses: During SD, the ascending arousal systems increase their activity to counteract the effects of increased sleep pressure. Increased activity of the ascending arousal systems increases BF activity during SD and results in a homeostatic sleep response. The actions of the ascending arousal systems are, in the BF, mediated by cholinergic neurons. The results show that overexpression of orexin leads to minor changes in vigilance state distribution, and to increased slow wave intrusions during prolonged wakefulness. During SD, the extracellular levels of serotonin and dopamine metabolites increased gradually, reaching a plateau from the third hour of SD. In contrast, extracellular BF histamine levels increased immediately when SD started and remained at the same level throughout the six hour SD, returning back to baseline immediately afterwards. On the baseline day, extracellular histamine levels showed a strong correlation with the amount of wakefulness, during both the light and the dark period. Although during wakefulness all studied ascending arousal systems increased their transmitter release in the BF, not all of them seem to be involved in the regulation of sleep homeostasis. The orexinergic, serotonergic, and dopaminergic systems show signs that they are involved in the regulation of sleep pressure, or at least that they are affected by sleep homeostasis. The increased sleepiness of mice overexpressing orexin might indicate that the orexinergic system is capable of influencing sleep homeostasis. The gradual increase in dopamine and serotonin turnover in the BF during SD shows that those transmitter systems are affected by increased sleep pressure, and they might counteract sleep pressure or add to it. On the other hand, histamine release in the BF is not affected by sleep pressure, and histamine perfusion into the BF does not result in a homeostatic response, showing that the histaminergic system is neither affected by nor able to manipulate sleep pressure in the BF, and thus shows no signs of being involved in sleep homeostasis mediated by the BF. Histamine perfusion into the BF led to theta-enriched cortical arousal, which did not result in a homeostatic sleep response. Because perfusion of other excitatory transmitters into the BF did induce a homeostatic response, the type of activation of the BF neurons might be crucial to result in the build-up of sleep pressure, and this is most likely receptor and neurotransmitter specific. Perfusing a histamine receptor 1 antagonist into the BF resulted in a dramatic decrease in wakefulness and cortical arousal, demonstrating that activation of the BF by histamine receptor 1 is essential in sustaining wakefulness and a high level of cortical activation. Finally, a specific neurotoxin was used to lesion the cholinergic neurons of the BF, after which the effects of histamine and histamine receptor 1 antagonist perfusion into the BF were ablated, indicating the importance of the cholinergic BF in mediating the wake-promoting effects of histamine. A lack of activation of the cholinergic BF by histamine may be important in initiating and maintaining NREM sleep.
According to these results, the BF might be the main route for histamine to promote wakefulness, it might also be the main route for the other ascending arousal systems to promote wakefulness, however this should be further investigated. A better understanding of the mechanisms by which the BF is activated and mediates this activation to the cortex might help us to find better therapies or medications for those suffering from sleep or wake disorders. Not available